In recent years, there has been a resurgence of drug-resistant strains of Mycobacterium tuberculosis, MDR-TB. This coupled with the fact that enclosed spaces, such as commercial aircraft among others, are effective locations to spread this serious respiratory disease, either purposely or accidentally, has influenced current CDC guidelines classifying MDR-TB as a Class C bioterrorism agent. The current vaccine for tuberculosis, BCG, while safe and effective at protecting young children, has been found only variably efficacious at protecting adults from this serious pulmonary disease. It is the purpose of this application to address the feasibility and provide proof of principle that a post-exposure (immunotherapeutic) vaccine can be developed that could inhibit the growth and associated pathogenesis of virulent forms of drug resistant M. tuberculosis, at least to an extent that the exposed individual is no longer infectious. This work will test vaccine candidates 72f, a recombinant polyprotein, and a mixture of low oxygen proteins both in MPL-SE adjuvant that have shown extremely promising early results by our consultants in mouse, guinea pig and monkey model systems. Mice will be exposed via aerosol to disease producing doses of M. tuberculosis H37Rv, then treated with various vaccine protocols at early disease phase, 30 days post exposure, and late disease phase 90 days post exposure, and monitored for approximately 120 days at 15 day intervals for disease. A guinea pig model, which resembles the disease seen in humans will also be utilized. Guinea pigs will be infected via aerosol with M. tuberculosis H37Rv and then vaccinated at 30 and 45 days and monitored for 15 weeks until signs of distress and weight loss occur during the remaining 10 months. The results of this study will be the basis for replicate studies using selected MDR-TB strains in a follow up phase to this work. Choice of one of the two post exposure therapeutic vaccine candidates, expansion of material production, testing expanded dose levels of the therapeutic aqent as well as, expanded safety and effectiveness studies are contemplated for a Phase II studies.